Background Dominant frequencies (DFs) of activation are higher in the atria of patients with persistent than paroxysmal atrial fibrillation (AF) and left-to-right atrial (LA-to-RA) DF gradients have been identified in both. However, whether such gradients are maintained as long-term persistent AF is established remains unexplored. We aimed at determining in-vivo the time-course in atrial DF values from paroxysmal to persistent AF in sheep, and test the hypothesis that a LA-to-RA DF difference is associated with LA drivers in persistent AF. Methods and Results AF was induced using RA tachypacing (N=8). Electrograms were obtained weekly from a RA lead and a loop recorder (ILR) implanted near the LA. DFs were determined for 5-sec-long electrograms (QRST subtracted) during AF in-vivo and in ex-vivo optical mapping. Underlying structural changes were compared to weight-matched controls (N=4). Following the first AF episode, DF increased gradually over a 2-week period (7±0.21 to 9.92±0.31 Hz, N=6, p<0.05). During 9–24 weeks of AF the DF values on the ILR were higher than the RA (10.6±0.08 vs. 9.3±0.1 Hz, respectively; N=7, p<0.0001). Subsequent optical mapping confirmed a DF gradient from posterior LA-to-RA (9.1±1.0 to 6.9±0.9 Hz. p<0.05) and demonstrated patterns of activation compatible with drifting rotors in the posterior LA (PLA). Persistent AF sheep showed significant enlargement of the PLA compared to controls. Conclusions In the sheep transition from paroxysmal to persistent AF shows continuous LA-to-RA DF gradients in-vivo together with enlargement of the PLA, which harbors the highest frequency domains and patterns of activation compatible with drifting rotors.

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